Overexpression of Serpin Squamous Cell Carcinoma Antigens in Psoriatic Skin

Squamous cell carcinoma antigen belongs to the serpin family and is used for the diagnosis and management of squamous cell carcinoma. We investigated the involvement of squamous cell carcinoma antigen in psoriasis, as it is always detected in the sera of patients with psoriasis. Squamous cell carcinoma antigen localization in psoriatic epidermis varied depending on its concentration in the patient's sera. When its level was low in serum, weak and scattered staining was observed in the granular layer. With a high concentration of squamous cell carcinoma antigen, strong staining through the suprabasal to granular layer and condensed staining around the plasma membrane or intracellular space was detected in the affected epidermis. Interestingly, squamous cell carcinoma antigen was abundant in nuclei of the granular layer cells and elongated rete ridges. Immunoelectron microscopy confirmed the localization of squamous cell carcinoma antigen in the nuclei as well as in the periphery of the cell membrane. A cDNA library was constructed from psoriatic epidermis and both clones, SCCA1 and SCCA2, were obtained. Attempts to raise specific antibodies or to prepare cRNA probes for SCCA1 and SCCA2 were unsuccessful because of their nearly identical structures. A primer pair from each reactive site sequence enabled us to give a distinctive product for SCCA1 and SCCA2 by reverse transcription polymerase chain reaction. Analysis using these primers demonstrated that the SCCA2 transcript was specifically expressed in psoriatic skin tissues. Our results suggest that overexpression of squamous cell carcinoma antigens is associated with the disease activity of psoriasis

THE ROLE OF SPORTIVE ACTIVITIES IN CHILDREN'S PERSONALITY DEVELOPMENT

The athlete is the main subject of performance generator and is being defined by a large number of attributes, some of which are characteristic for achieving it. He can develop only if certain conditions are met both in terms of correlating interdependent attributes, qualities – skills and the environmental factors, social, material, teaching. The relationships between members of a community are subject to numerous factors such as: psychological peculiarities of the athletes, the general orientation, the reasons of the proposed activity, attitudes "built" in life and the society in which they live. There are a few things to note: first, the game strengthens a child physically, it embodies the taste of performance and the means to achieve it. Secondly, the game creates teamwork skills to synchronize their actions with those of others to achieve a common goal. A third, the game causes a good mood, cheerful, giving the people the ability to clear their heads and have fun giving more lust for life. Rolul jocurilor sportive in dezvoltarea personalitatii copiilor. Sportivul care este principalul subiect generator al performanţei este definit de un număr foarte mare de atribute dintre care unele sunt caracteristice pentru realizarea acesteia. El se poate dezvolta numai dacă sunt îndeplinite anumite condiţii atât în privinţa corelării interdependente a atributelor –însusiri, calităţi –aptitudini, cât şi a determinatelor ambientale, sociale, materiale, pedagogice. Relatiile care se stabilesc între membrii unei colectivităţi sunt condiţionate de numeroşi factori . Există câteva lucruri de remarcat: în primul rând, jocul fortifică un copil din punct de vedere fizic, îi imprimă gustul performanţelor precum şi mijloacele de a le realiza. În al doilea rând, jocul creează deprinderi pentru lucrul în echipă, pentru sincronizarea acţiunilor proprii cu ale altora, în vederea atingerii unui scop comun. Un al treilea rând, jocul provoacă o stare de bună dispoziţie, de voie bună, oferindu-i omului posibilitatea de a uita pentru un timp de toate celelalte şi de a se distra, dându-i parcă mai multă poftă de viaţă.  Cuvinte cheie: sportivi, jocuri sportive, relatiile de joc, organizare

The POT1-TPP1 telomere complex is a telomerase processivity factor

Telomeres were originally defined as chromosome caps that prevent the natural ends of linear chromosomes from undergoing deleterious degradation and fusion events. POT1 ( protection of telomeres) protein binds the single-stranded G-rich DNA overhangs at human chromosome ends and suppresses unwanted DNA repair activities. TPP1 is a previously identified binding partner of POT1 that has been proposed to form part of a six-protein shelterin complex at telomeres. Here, the crystal structure of a domain of human TPP1 reveals an oligonucleotide/oligosaccharide-binding fold that is structurally similar to the beta-subunit of the telomere end-binding protein of a ciliated protozoan, suggesting that TPP1 is the missing beta-subunit of human POT1 protein. Telomeric DNA end-binding proteins have generally been found to inhibit rather than stimulate the action of the chromosome end-replicating enzyme, telomerase. In contrast, we find that TPP1 and POT1 form a complex with telomeric DNA that increases the activity and processivity of the human telomerase core enzyme. We propose that POT1 - TPP1 switches from inhibiting telomerase access to the telomere, as a component of shelterin, to serving as a processivity factor for telomerase during telomere extension.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62923/1/nature05454.pd

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Variation in general supportive and preventive intensive care management of traumatic brain injury: a survey in 66 neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study

Abstract Background General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers. Methods We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment. Results The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36–40 mmHg (4.8–5.3 kPa) in case of controlled intracranial pressure (ICP) < 20 mmHg (n = 45, 69%) and PaCO2 target of 30–35 mmHg (4–4.7 kPa) in case of raised ICP (n = 40, 62%). Almost all respondents indicated to generally treat fever (n = 65, 98%) with paracetamol (n = 61, 92%) and/or external cooling (n = 49, 74%). Conventional glucose management (n = 43, 66%) was preferred over tight glycemic control (n = 18, 28%). More than half of the respondents indicated to aim for full caloric replacement within 7 days (n = 43, 66%) using enteral nutrition (n = 60, 92%). Indications for and duration of seizure prophylaxis varied, and levetiracetam was mostly reported as the agent of choice for both seizure prophylaxis (n = 32, 49%) and treatment (n = 40, 61%). Conclusions Practice preferences vary substantially regarding general supportive and preventive measures in TBI patients at ICUs of European neurotrauma centers. These results provide an opportunity for future comparative effectiveness research, since a more evidence-based uniformity in good practices in general ICU management could have a major impact on TBI outcome

Variation in neurosurgical management of traumatic brain injury

Background: Neurosurgical management of traumatic brain injury (TBI) is challenging, with only low-quality evidence. We aimed to explore differences in neurosurgical strategies for TBI across Europe. Methods: A survey was sent to 68 centers participating in the Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. The questionnaire contained 21 questions, including the decision when to operate (or not) on traumatic acute subdural hematoma (ASDH) and intracerebral hematoma (ICH), and when to perform a decompressive craniectomy (DC) in raised intracranial pressure (ICP). Results: The survey was completed by 68 centers (100%). On average, 10 neurosurgeons work in each trauma center. In all centers, a neurosurgeon was available within 30 min. Forty percent of responders reported a thickness or volume threshold for evacuation of an ASDH. Most responders (78%) decide on a primary DC in evacuating an ASDH during the operation, when swelling is present. For ICH, 3% would perform an evacuation directly to prevent secondary deterioration and 66% only in case of clinical deterioration. Most respondents (91%) reported to consider a DC for refractory high ICP. The reported cut-off ICP for DC in refractory high ICP, however, differed: 60% uses 25 mmHg, 18% 30 mmHg, and 17% 20 mmHg. Treatment strategies varied substantially between regions, specifically for the threshold for ASDH surgery and DC for refractory raised ICP. Also within center variation was present: 31% reported variation within the hospital for inserting an ICP monitor and 43% for evacuating mass lesions. Conclusion: Despite a homogeneous organization, considerable practice variation exists of neurosurgical strategies for TBI in Europe. These results provide an incentive for comparative effectiveness research to determine elements of effective neurosurgical care

Two year efficacy of trabecular micro-bypass stent in patients with glaucoma and cataract

Purpose: To evaluate intraocular pressure (IOP) and number of IOP lowering medications in open angle glaucoma patients with up to 24 months follow up after phacoemulsification with (iStent) or without (control) a first-generation trabecular micro-bypass stent (Glaukos Corporation, Laguna Hills). Methods: This is a retrospective cohort study of 213 patients (276 eyes) with open angle glaucoma after phacoemulsification with (142 eyes) or without iStent implantation. Mean age was 71.9 years in the iStent group and 72.9 years in the control group. 117 individuals (55%) were female, of these 58 (40.9%) were in the iStent group. Data of 247 eyes (128 iStent) were available at 6 months [6M], 222 (123 iStent) at 12 months [12M], and 147 (91 iStent) at 24 months [24M]. Results: Number of medications prior to surgery were 2.1 in the iStent group and 1.2 in the control group (mean difference=0.9, 95% confidence interval (CI) [0.5,1.2], p O.0001); at 6M 1.5 and 1.4, at 12M 1.5 and 1.5, and at 24M 1.5 and 1.6, respectively. Prior to surgery, IOP was 18.0 in the iStent group and 15.8 in the control group (mean difference=2.3, 95% CI [1.2, 3.4], p\u3c0.0001); at 6M 15.2 and 14.3, at 12M 14.8 and 13.7, and at 24M 14.6 and 14.7 mm Hg, respectively. The mean decrease in number of medications was significantly greater in the iStent group than the control group between pre-op and all 3 follow-up times: 6M mean=0.8 (95% CI [0.5,1.0], p\u3c0.0001); 12M mean=0.7 (95% CI [0.5, 0.9], p \u3c0.0001); and 24M mean=0.8 (95% CI [0.5,1.1], p\u3c0.0001). The mean decrease in IOP was also significantly greater in the iStent group than the control group between preop and all 3 follow-up times: 6M mean=1.4 (95% CI [0.2, 2.5], p=0.0195); 12M mean=1.7 (95% CI [0.4, 3.1], p=0.0139); and 24M mean=2.8 (95% CI [1.2, 4.5], p=0.0006). Conclusions: Eyes in both groups experienced an IOP lowering effect that was sustained over 24 months, but this was significantly greater in the iStent group. Eyes that received iStent had a significantly greater reduction in the number of medications than the control group, at every time point after surgery. Additionally, at every time point after surgery, the mean number of medications in the iStent group was fewer than pre-op, while the mean number of medications in the control group was more than pre-op